The overall goal of this Outstanding Investigator Award (OIA) application is to identify and validate novel targets and therapeutic agents for human cancers with mutant KRas. Overwhelming evidence has accumulated over the last 3 decades that demonstrates significant contributions of mutant KRas to human cancer pathogenesis and patient tumor resistance to therapy, yet no mutant KRas inhibitors have reached clinical trials. The NCI has recognized this as a major challenge and obstacle to making significant progress to clinical outcomes. This OIA application builds on the PI's track-record and expertise in the area of chemical biology and drug discovery in the Ras field and proposes a comprehensive research program focused on targeting KRas and its signaling pathways to develop novel agents that are specific for human tumors that depend on mutant KRas for survival and malignancy. The application will engage in research that tackles this challenging problem on many fronts with several innovative approaches assembled under 4 programs focusing on: 1) Directly targeting mutant KRas by identifying small molecules that bind mutant KRas and lower its affinity for GTP, and those that bind KRas and inhibit its binding to its effectors; 2) Indirectly targeting KRas by inhibiting its prenylation with dual FT and GGT-1 inhibitors in human cancers that depend on mutant KRas as well as targeting downstream targets required for KRas transformation with GGT-1 inhibitors in human tumors that depend on geranylgeraylated proteins, 3) Understanding the mechanism by which mutant KRas suppresses p53, identifying novel druggable targets in this pathway and overcoming mt KRas dependency. This will include mechanistic studies as well as identifying signaling networks that mt KRas relies on to cause cancer with an emphasis on kinases whose suppression is synthetically lethal in tumors that depend on mt KRas for survival, 4) Discovering proteins that are expressed exclusively on the surface of human tumor cells that harbor mt KRas with the ultimate goal of developing tools to detect human tumors cells with KRas mutations, to follow treatment progress and to use the identified proteins as targets to design novel anti-cancer drugs. The proposed OIA research programs will result in significant discoveries that will lead to therapies that specifically target patients whose tumors harbor mutant KRas. This will contribute to overcoming the mutant KRas challenge that is of high priority and long term relevance to the mission of the NCI.